Influenza virus is a large RNA virus having a core of helical symmetry containing a soluble nucleoprotein antigen. The virion has a membrane envelope with spikes containing two viral glycoproteins, one having hemagglutinating activity (HA) and one having neuraminidase activity (NA). Influenza virus attaches to a specific glycoprotein receptor for the hemagglutinin on the cell surface. The virus possesses an unusual genomic structure of RNA segments, which reshuffle upon each cycle of infection. Influenza is a virus of the respiratory tract, and is an etiological agent of acute bronchitis, pneumonia, croup, and influenza. One of the worst epidemics ever was the virus influenza epidemic early in the twentieth century. Current therapy includes amantadine, which has various undesirable side effects.
Applicants have discovered that a variety of known compounds are effective for the prevention and treatment of influenza infection. Treatment with glutathione (GSH), glutathione disulfide (GSSG), N-acetyl-L-cysteine or ascorbate-2-phosphate, or any combination thereof, with or without antioxidants, is suitable for the prevention or treatment of influenza virus infection.
Glutathione is the tripeptide gamma-L-Glu-L-Cys-Gly, of the structure ##STR1##
Among other natural functions, GSH is a biological reducing agent in thiol-dependent reactions. As an exogenously supplied drug, it potentiates and enhances the efficacy of various antineoplastic agents, presumably through nucleophilic thioether formation or oxidation-reduction reactions. See, e.g., Arrick, B. A. et al. Cancer Research 44:4224 (1984).
Glutathione (GSH) is an essential compound in the gamma-glutamyl cycle, which probably functions to transport amino acids through the cell membrane. Glutathione is also known to act as a cofactor in a variety of enzymatic reactions, including the glyoxylase reaction, the cis-trans isomerization of maleylacetoacetate to fumarylacetoacetate, and the formaldehyde dehydrogenase reaction.
Substantial evidence points to the role of GSH in reducing cellular damage from reactive oxygen species, typically generated by ionizing radiation. The exact mechanism for this effect is not understood. Intriguing evidence suggests potential therapy of certain cancers. For example, the ultimate carcinogenic form of chemical carcinogens is typically electrophiles, which can be detoxified by reactions catalyzed by GSH S-transferases. Administration of large oral dosages of GSH to rats with liver cancer results in substantial regression of the liver tumor. As noted above, GSH potentiates the efficacy of various antineoplastic agents. There is some evidence for a significant link between GSH and calcium homeostasis. For a summary of GSH metabolism, see Meister, A. et al., Ann. Rev. Biochem. 52:711 (1983).
Glutathione disulfide (GSSG) is the oxidized dimer of glutathione (GSH). GSSG occurs naturally in the oxidation-reduction cycle for the formation of thioethers.
N-Acetyl-L-cysteine is commonly known as a mucolytic agent. It also functions as a reducing sulfur compound in certain protein purifications, an agent for treating lower respiratory tract infections in children, as well as chronic bronchitis, HIV infection, chronic cardiorespiratory disorders and fulminant hepatic failure. It is also known as a disinfectant for Hepatitis B virus, and an agent that enhances the response to interferon-alpha in chronic Hepatitis C cases.
Ascorbate-2-phosphate is a stable derivative of ascorbic acid (vitamin C). It has the structure ##STR2## Vitamin C is widely used as an ingredient of cosmetic compositions, such as skin creams and lotions, as well as a common dietary supplement. A variety of unrelated uses are also known, including uses related to pickling and preservation of meat and seafood, improved dough for making breads, soy seasoning for fermented soybeans, sweetening agent, nerve growth factor potentiator, chemical decontaminant for a nuclear plant, a component in compositions for adding texture and color stability to frozen vegetables, an ingredient for an electroplating bath suitable for electroplating electronic parts, and part of a process for making fine palladiuum particles.
In the practice of the present invention, the antiviral agents are supplied directly to cells to reduce infection and viral particle production. Current methods for prevention of influenza infection involve immunization, which is not completely effective, is costly and has associated risks. Glutathione, glutathione disulfide, N-acetyl-L-cysteine, ascorbate-2-phosphate, or any combination thereof, are safe natural products for the treatment of influenza virus infection and also provide a novel approach to prevention. These compositions can be supplied directly to the epithelial cells which are the potential site of infection in a lozenge, drinking solution, mouth rinse or nasal spray.